The goal of these studies is to understand the cellular mechanisms that underlie degenerative/regenerative events in the CNS. Towards this end we have developed two model systems. The first builds upon our work from the prior period of support during which we showed significant reorganization of dendritic architecture of piriform cortex pyramidal neurons following transection of the lateral olfactory tract (LOT). We now propose to test the following hypotheses: (1a) There are changes in the architecture of dendritic spines of denervated neurons that increase the excitability of the neuron and thus compensate for the reduced number of synapses. (1b) The expression in subpopulations of neurons of putative neuroactive peptides/transmitters is differentially influenced by LOT transections and that the magnitude of a response reflects, in part, the extent of surviving synaptic input. The second model uses a recently developed in vitro preparation in which we maintain, both alone and in co-culture, olfactory receptor cell neurons and olfactory bulb neurons. Using the in vitro model we will test the hypotheses: (2a) that regenerative attempts by a transected axon are dependent upon the placement of the transection, the age of the neuron, and the prior development of other collaterals proximal to the soma; (2b) that the response of a postsynaptic neuron to the loss of only some of its synaptic input is dependent, in part, upon the amount and distribution of remaining synaptic input (cf. 1b); and (2c) that the unique ability of the olfactory system to sustain neurogenesis, outgrowth of axons and synaptogenesis reflects, in part, the properties of glial cells found in both the olfactory nerve and bulb. These studies will provide new insights into basic cellular events leading to degeneration and regeneration in the CNS. Specifically, these studies will provide new information important for resolving controversies about the cell-to-cell interactions that may occur during degenerative/regenerative events in the CNS. Ultimately, that knowledge is crucial for the development of effective strategies directed at improving neurological outcome following injury to the human CNS.